Drug does not improve set of cardiovascular outcomes for diastolic heart failure

A drug that blocks the action of a key hormone did not significantly improve a set of cardiovascular outcomes for patients with diastolic heart failure, a condition in which the heart is stiffer than normal and has problems filling with blood, according to a study supported by the National Institutes of Health.

In terms of the study’s primary aim, the results showed no difference in the overall combined endpoint treatments. The study did reduce the rate of heart failure hospitalizations, which was one of the endpoints, in the target population.

The drug, spironolactone, blocks the action of the hormone aldosterone, which is produced in excess in heart failure. The inexpensive generic drug currently is approved to treat patients with systolic heart failure, in which the heart muscle's pumping ability is reduced. There is no specific therapy for diastolic heart failure.

In the current trial, spironolactone did not improve the combined primary endpoints of cardiovascular death, hospitalization for heart failure, or aborted cardiac arrest. Aborted cardiac arrest is a stopped heart that is restarted by CPR or an implanted device.

NIH's National Heart, Lung, and Blood Institute (NHLBI) supported the work, which was published in the April 10 edition of the New England Journal of Medicine. The paper represents the primary results of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Diastolic heart failure, also known as heart failure with preserved systolic function, is a common heart condition accounting for about half of all heart failure cases. The Centers for Disease Control and Prevention estimates that 5.7 million people in the United States have heart failure.

“Heart failure is the most common reason for hospital admissions in the Medicare population, and diastolic heart failure accounts for at least half of these admissions,” said Dr. Bertram Pitt of the University of Michigan, Ann Arbor, TOPCAT’s study chairman. “Given the high financial and societal costs of these hospitalizations, there is a critical need to find treatments to reduce them. However, no effective therapy for diastolic heart failure has been found to date.”

The New England Research Institute and Brigham and Women’s Hospital in Boston led the multi-center international research effort involving 3,445 participants, which makes it one of the largestdiastolic heart failure trials to date. Researchers enrolled participants in 270 sites spread across the United States, Canada, Argentina, Brazil, the Republic of Georgia, and Russia. Trial participants were randomly placed on spironolactone or a matching placebo and followed for an average of three years.

For the spironolactone group, 319 participants experienced one of the primary outcomes versus 351 in the placebo group, a 9 percent reduction that did not reach statistical significance. For heart failure hospitalizations, 206 people in the spironolactone group were hospitalized versus 245 people in the placebo group, a statistically significant reduction of 16 percent.

“Although TOPCAT did not significantly decrease the combined endpoint or cardiovascular death, spironolactone is the first drug shown to reduce heart failure hospitalizations in this vulnerable population,” said Brigham and Women’s Hospital's Dr. Marc Pfeffer, the principal investigator.

Spironolactone showed no difference in other serious adverse events, such as dialysis, compared to placebo, although participants taking the drug had higher increased potassium levels than the control group. While use of spironolactone carries the risk of elevated blood potassium levels or reduced kidney function, these risks were low in TOPCAT and can be reduced in clinical practice with careful monitoring.

“This study is an important step in the effort to find effective treatments for diastolic heart failure patients," said Dr. Michael Lauer, director of the NHLBI's Division of Cardiovascular Sciences. "The study examined a broad cross-section of diastolic heart failure patients, and further data analysis may offer clues about sub groups that may particularly benefit from spironolactone treatment."

Initial analysis showed potentially different outcomes based on how a participant qualified for the study. Researchers used two methods to determine which patients with heart failure were eligible to enroll in the study. One method required looked for elevated levels of the hormone BNP, which is associated with more severe heart failure. The other method required looked at a person's history of heart failure hospitalization within the last year.

The study showed that participants enrolled via elevated BNP measurements who received spironolactone fared better in the composite of main outcomes than the BNP group enrolled in the placebo arm. Of the patients enrolled via the BNP criteria, there were 78 patients with events in the spironolactone arm and 116 patients with events in placebo group.

Further analysis showed significant geographic variation in event rates. For patients enrolled in Russia and the Republic of Georgia, 78 patients (10 percent) in the spironolactone arm and 71 patients (8 percent) in the placebo arm reached the composite primary endpoints. For patients in North and South America, 242 patients (27 percent) in the spironolactone arm and 280 patients (4 percent) in the placebo arm reached the composite primary endpoints.

The study was funded through NHLBI contract HHSN268200425207C.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH):
NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.